BACTERIA

Structure and composition

Always: 70S ribosomes, peptidoglycan cell wall, plasma membrane, cytoplasm, no nucleus, no membrane-bound organelles, suspended looped DNA, glycogen granules and lipid droplets.

Sometimes: Flagella, pilli, plasmids, capsule, mesosomes, thylakoids (cyanobacteria only).

Bacteria are usually hypertonic to the solution they are suspended in, so water will move into them (hence the need for a cell wall). Can be spore-forming.

Cocci – sphere

Bacilli – rod

Vibrio – comma-shaped

Spirilla/spirochete – twisted

Obligate aerobes – need O2

Facultative anaerobes – will use O2 but don’t need it for survival

Obligate anaerobes – cannot respire in the presence of O2

Bacterial cell walls

Made of peptidoglycan; parallel polysaccharide chains with short peptide cross-linkages. Forms an enormous molecule with a net-like structure. 2 types: 

Gram-negative:

No teichoic acid; thin layer of peptidoglycan; peptidoglycan layer is between 2 membrane layers. Has an outer layer of lipopolysaccharides (releases endotoxins when broken down). Most crystal violet washes off as it cannot bind to teichoic acid. Any that does bind is readily decolourised and replaced by red safranin so the cells appear red/pink. 

Gram-positive:

Has teichoic acid; thick layer of peptidoglycan. The crystal violet binds to teichoic acid and resists decolouring in the rest of the process, leaving the cells a purple/blue colour.

Gram staining:

Heat-fixed/air dried -> crystal violet -> Gram’s or Lugol’s iodine (fixes CV) -> acetone (decolourises CV) -> red safranin (counter-stain) -> wash.

Toxins

Endotoxin (Gram-negative only):

Lipopolysaccharides which form the outer layer of Gram-negative bacteria release endotoxins when the bacterial cell wall is destroyed. Toxins are coded for by plasmids. Cause symptoms such as fever, vomiting and diarrhoea. Only usually cause death indirectly; e.g. by dehydration.

Exotoxin (Gram-negative and Gram-positive):

Can be both secreted by the cell or released during cell lysis. May destroy host cells are disrupt cellular metabolism; e.g. by interrupting neurotransmission. Susceptible to antibodies but toxins are often fatal before enough antibodies can be produced. Allow further spread of bacteria as tissues are broken down. Therefore may be local or systemic. Can be destroyed by heating. Rarely cause fever.

Reproduction

Generation time – the time between cell divisons (usually by binary fission).

Transformation – a short piece of DNA is released by a donor and taken up by a recipient (replacing a similar piece of DNA within it).

Transduction – a short piece of DNA is transferred between bacteria by a bacteriophage (virus), sometimes by mistake during infection as it is incorporated into the viral coat.

Conjugation – the donor cell (F+) produces a sex pilus along which DNA is transferred to the recipient (F-). The sex pilus is coded for by a plasmid.

Things I’m learning at med school: Malaria

Basic facts:

Protozoan disease of the genus Plasmodium.

Transmitted only by female Anopheles mosquitos.

4 main species: P. falciparum, P. vivax. P. ovale and P. malariae (P. knowlesi may also infect humans but rarely does so, more commonly affecting monkeys).

When inside RBCs the parasite consumes intracellular proteins (particularly haemoglobin). As haem is potentially toxic, plasmodium detoxifies it to a biologically inert form (haemozoin), which can be seen as a coloured pigment.

Plasmodium alters the RBC membrane, making it irregular in shape, more antigenic and less deformable.

Mechanism:

Mosquito inoculates plasmodial sporozoites from its salivary glands during a blood meal and motile forms of the parasite are carried rapidly in the bloodstream to the liver where they invade hepatic cells and begin a period of asexual reproduction. An amplification process produces 10,000 – 30,000 daughter merozoites.

Infected liver cells swell and burst, discharging motile merozoites into the bloodstream. RBCs are then invaded and the merozoite takes a ring form known as a trophozoite. The trophozoite multiplies, consumes haemoglobin and fills the RBC; the RBC is now known as a schizont (shown in the image above). When the RBCs rupture, daughter merozoites are released, capable of invading more RBCs and repeating the cycle.

Some parasites may develop into longer-lived gametocytes that can transmit malaria. These may be ingested by another mosquito, which forms a zygote in the insect. It matures and migrates to the salivary glands where it can be transmitted to another human host.

 * * *

In P. vivax and P. ovale, a proportion of the intrahepatic forms remain dormant from 3 weeks – 1 year (or more) before reproduction begins (hypnozoites). These are the cause of relapses that characterise infection with these two species.

In P. falciparum, protuberances appear on the surface of RBCs; a specific type of adhesion protein that mediates attachment to receptors on venular and capillary endothelium (cytoadherence). This can lead to blockage and sequestration of RBCs in vital organs. May also adhere to other infected RBCs (agglutination) or non-infected RBCs (rosetting = decreased deformability). Sequestration allows parasites to develop out of reach of splenic processing and filtration, therefore only younger ring forms of asexual parasites are seen circulating in peripheral blood in P. falciparum, so peripheral parasitsaemia is an underestimated value.

Host response:

Splenic filtration is accelerated (becomes enlarged in later stages).

When schizont ruptures interleukin-1 is released, which causes a fever.

Temperatures exceeding 40◦C damage mature parasites, which synchronise the malarial cycle and if left untreated will present as a tertian fever (except in P. malariae which is quartan).

First symptoms: Fever, malaise, headache, fatigue, abdominal discomfort, muscle aches, nausea, vomiting, orthostatic hypertension. May have: mild anaemia, palpable spleen, slightly enlarged liver, mild jaundice. 

Severe P. falciparum: Cerebral malaria due to sequestration and agglutination. May cause coma. ~20% adult mortality.

Acidosis due to accumulation of organic acids (e.g. lactic acid released from RBCs).

Hypoglycaemia as the liver is not maintaining adequate glucose levels due to failure of hepatic gluconeogenesis. There is also increased glucose consumption by host and parasite.

Other symptoms include anaemia, renal failure, pulmonary oedema, hypotension/shock, haemorrhaging, haemoglobinuria and jaundice.

Diagnosis:

Relies on asexual parasite forms in peripheral blood smears (thick and thin; x1000 oil immersion).

Parasitsaemia expressed as number of parasitised erythocytes per 1000 RBCs.

Antibody stick or card tests can also be used using finger prick blood samples.

Antimalarial Drugs:

Quinidine – Trophozoite stage. Kills gametocytes of P. v, P. o and P. m.

Chloroquine – As above but earlier in the asexual cycle.

Others include amodiaquine, mefloquine, tetra/doxycycline, halofantrine.

Prophylaxis – malarone, chloroquine, doxycycline (these will reduce the incidence of P. f infection but cannot treat it once infected).

Intra-abdominal Haemorrhage 

A: Cullen’s sign (bruising around the navel (periumbilical ecchymosis)) 

B: Turner’s sign (bruising on the abdominal flank)

Cullen’s and Turner’s signs have been described with intra-abdominal haemorrhage most commonly associated with pancreatitis. Rare associations include ectopic pregnancy, malignant disease (liver, abdominal metastasis), perforated duodenal ulcer, liver abscess, and splenic rupture.

Things I’m learning at med school: Cholera

Basic facts:

Vibrio cholerae; bacteria

Comma shaped bacillus (i.e. vibrios)

Causes acute intestinal infection

Gram-negative

Usually has a 24-48 hour incubation period

Primarily transmitted through the faecal-oral route

Occurs mainly in Africa due to poor sanitation

Mechanism:

Most bacteria do not survive the stomach acid (therefore a vast exposure is required for infection to occur).

Those that do survive the acid shut down protein production to conserve energy until they reach the small intestine. Here they will each grow a flagellum to propel them through the thick mucosal wall where they may thrive (held in position by pili).

The bacteria then produce an enterotoxin (a protein toxin released by a microorganism in the intestine). This binds to the surface of intestinal epithelial cells and is taken into the cell via receptor-mediated endocytosis.

To put it simply, it is metabolised within the cell, leading to increased cAMP concentration, which massively activates cytosolic PKA (protein kinase A). These active PKA then open up the cystic fibrosis transmembrane conductance regulator (CFTR) proteins, which leads to Ca²⁺ being pumped out into the intestinal lumen, which in turn leads to secretion of H₂O, Na⁺, K⁺, and HCO₃^-.

In addition, The entry of Na⁺ and consequently the entry of water into enterocytes are diminished. The combined effects result in rapid fluid loss from the intestine, up to 2 liters per hour, leading to severe dehydration.

Symptoms:

There are few symptoms specific to cholera, aside from a rapid onset of severe diarrhoea, abdominal cramping, a rice-water stool and often metabolic acidosis (due to the secretion of HCO₃^-), which can also lead to vomiting.

All other signs/symptoms are that of dehydration:

Dry mucous membranes

Skin tugor

Sunken eyes

Lack of tears

Low urine output

Low BP

Rapid pulse

Delayed capillary refill

Treatment:

Treating cholera is incredibly simple, only requiring rehydration of water and electrolytes

Oral rehydration therapy (ORT) - This is the easiest treatment for cholera and is perfectly suitable for water rehydration however it does not provide any electrolytes. This is a mixture of water, glucose and salt (adding a mashed banana will provide potassium) - it is similar to normal saline but with glucose to increase water absorption.

IV Lactated Ringer’s solution (or Hartmann’s solution) - This is similar to ORT but it will also provide the required electrolytes and correct metabolic acidosis. The components of this are: sodium, potassium, chloride, calcium and lactate.

Antibacterials (such as tetracycline) can be administered in the treatment of cholera however they are not necessary for a recovery; they reduce the duration of the disease and improve symptoms.

Diffuse oesophageal spasm (DES) or ‘corkscrew oesophagus’

Normally, the oesophagus transports food from the upper oesophageal sphincter towards the stomach through waves of coordinated muscle contraction (peristalsis).

DES occurs when these muscular contractions are uncoordinated, with several areas of the oesophagus contracting simultaneously when the patient swallows (defined as occurring at least 20% of the time).

Cause: There are several speculated causes of DES, such as visceral hypersensitivity and neurological abnormalities. A large majority of cases are seen to occur in patients with gastroesophageal reflux (even more so in those undergoing oesophageal manometry). There is an increased incidence in patients over 50.

Presentation: It may present with a chest pain that mimics angina, usually felt in the anterior chest, throat or epigastrium and can radiate to the neck, back or upper arms (as with cardiac chest pain). Other symptoms may include dysphagia (difficulty swallowing), weightloss (due to pain/dysphagia) and reflux-related symptoms (e.g. heartburn, regurgitation, cough and hoarseness).

A barium swallow as shown in the image above can demonstrate the appearance of a spasm however oesophageal manometry (a test used to measure the function of the lower oesophageal sphincter (the valve that prevents reflux of gastric acid into the oesophagus) and the muscles of the oesophagus) is the preferred investigation.

Treatment: Avoidance of precipitating factors e.g. hot or cold food;

Muscle relaxants may be effective, e.g. isosorbide mononitrate and nifedipine;

Proton pump inhibitors may be needed if there is associated reflux;

Endoscopic balloon dilatation of the gastro-oesophageal sphincter;

Laparoscopic Heller myotomy (in which the muscles of the cardia (lower oesophageal sphincter or LES) are cut, allowing food and liquids to pass to the stomach). This is thought to be the surgical treatment of choice for diffuse oesophageal spasm.

SEM of rod (blue) and cone (green) cells of the retina.

To A level standard:

Rod cells are sensitive to low light levels and produce low-clarity black and white vision. Cone cells are sensitive to higher levels of light and produce sharp, high-clarity trichromatic colour vision. The retina consists primarily of rod cells, with cone cells being found more so in the fovea.

The rod cell contains a light absorbing pigment known as rhodopsin, this is the photoreceptor in humans. It has two parts, a lipoprotein known as opsin and a vitamin A derivative known as retinal.

Retinal can exist in two isometric forms, cis (when in darkness) and trans (when in light).

Mechanism:

When rhodopsin absorbs light, retinal changes from cis to trans, causing the opsin and retinal parts to lyse. This is known as bleaching. The lysing of opsin brings about a cascade of reactions, activating G protein transducin which brings about a further messenger cascade. The importance of this is that it brings about changes in the rod cell membrane, closing Na+ channels so that the cell becomes hyperpolarised.

The rod cell synapses with a bipolar cell and secretes glutamate into the synaptic cleft which inhibits the bipolar cell (prevents it from depolarising). The hyperpolarisation of the rod cell stops such secretion of glutamate, resulting in a generator potential/depolarisation of the bipolar cell. If enough stimulation occurs (by spatial summation*) then the electrical current will be passed onto a ganglion cell (this is a sensory neurone and it synapses with the bipolar cell) and an action potential will be carried to the visual cortex where the visual information will be processed and an appropriate response will occur.

*Spatial summation - multiple rod cells synapse with the bipolar cell, so the more rod cells that are hyperpolarised, the more likely it is for a generator potential (and thus action potential) to occur.

Tendinous cords of the heart AKA heart strings. 

These are located inside the ventricles of the human heart and their purpose is to prevent the atrioventricular valves prolapsing into the atria during ventricular contraction (systole).

The above image is a light micrograph of a microscopic cyst containing Toxoplasma gondii parasites (stained red) in brain tissue.

Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii.

The parasite primarily resides in cats however humans (and other mammals) may also be infected. Contact with domesticated cats (spread in faeces) and digestion of raw meat are the main causes for infection in humans however in healthy adults the parasite will usually only lead to mild flu-like symptoms in the first weeks after exposure before the infection enters a latent phase, forming cysts in nervous and muscle tissues. The individual will then (unless immunocompromised) remain completely asymptomatic thereafter (if not so already). Once infected, a person is immune from further infection for life.

Infection is much more concerning in those with a weakened immune system, such as pregnant women and those already suffering from infection or disease (e.g. with AIDS or TB). In such cases toxoplasmosis can lead to serious illness and potential fatality. Toxoplasmosis can also be transmitted from mother to child, leading to severe complications as the infant is vulnerable and yet to develop a functioning immune system. These complications often appear at birth (or during gestation) however symptoms may not appear until a later stage in life, with greater severity than would usually be seen in an individual (more on this in another post).

The parasite can cause encephalitis (inflammation of the brain), neurologic diseases, can affect the heart, liver, inner ears, and eyes (chorioretinitis, necrotizing retinochoroiditis). Recent research has also linked toxoplasmosis to brain cancer, attention deficit hyperactivity disorder, obsessive compulsive disorder and schizophrenia.

‘In 11 of 19 scientific studies, T. gondii antibody levels were found to be significantly higher in individuals affected by first-incidence schizophrenia than in unaffected persons. Individuals with schizophrenia are also more likely to report a clinical history of toxoplasmosis than those in the general population.’

‘Recent work at the University of Leeds has found the parasite produces an enzyme with tyrosine hydroxylase and phenylalanine hydroxylase activity. This enzyme may contribute to the behavioral changes observed in toxoplasmosis by altering the production of dopamine, a neurotransmitter involved in mood, sociability, attention, motivation and sleep patterns.’

(Source: eviscerator)

Postmortem angiogram of coronary arteries.